Breast cancer accounts for nearly one quarter of all cancer diagnoses and is the principle cause of cancer-related mortality in women worldwide (1, 2). Currently, treatment selection for breast cancer is based on pathological information and histological grade, and on the expression status of the estrogen (ER), progesterone (PR) and epidermal growth factor 2 (HER2/neu) receptors, where targeted treatments blocking receptor function have made improvement in overall survival (1, 3). Indeed expression of ER and/or PR is a good prognostic factor and predictive indicator for benefit from endocrine therapies and although HER2 overexpression connotes adverse prognosis, patients greatly benefit from anti-HER2 targeted treatments (4, 5).
In contrast, the triple negative subclass of breast cancers (TNBC), defined by the absence of the ER and PR receptors and the lack of HER2 amplification, have no targeted treatment options, are highly aggressive and exhibit poor prognosis (6, 7). Although breast cancer research has pioneered and highlights the clinical benefits of targeted treatments, further identification of drivers and associated signaling pathways, particularly for TNBC and HER2 breast cancers, are needed to instruct the development of targeted therapies, to extend disease-free survival and improve the lives of cancer patients.
Casein kinase-1 delta (CK1δ) and epsilon (CK1ε) are two highly related serine/threonine kinases known to regulate diverse cellular processes, including circadian rhythm, membrane trafficking and the cytoskeleton, and both have been implicated in cancer (8-11). For example, myristolated CK1ε is sufficient to transform mammary epithelial cells in vitro whereas expression of a dominant-negative mutant of CK1δ impairs SV40-induced mammary carcinogenesis in vivo (12). As kinases CK1δ and CK1ε are eminently tractable for small molecule drug discovery. Nevertheless, the contribution of these kinases to human cancer is poorly understood and the non-selective nature of previously reported CK1δ/CK1ε inhibitors has impeded validation of these kinases as anti-cancer targets (9, 13-15). Indeed, pharmacological effects originally ascribed to inhibition of CK1δ/CK1ε are now known to be due to off-target action of the non-selective inhibitors employed (13, 16).